Exercise and Cognitive Function in Alzheimer?s Disease Progression: Role of The Vascular Endothelium Abstract: Alzheimer?s disease (AD), and its prodromal stage amnestic mild cognitive impairment (MCI), are devastating neurodegenerative diseases for which there are few treatments that slow the progression of cognitive decline. Importantly, through unknown mechanisms, physical exercise reduces the risk of AD and cognitive decline in older adults and patients with MCI. Recent evidence suggests that the beneficial effect of exercise on the rate of cognitive decline in healthy, older adults is largely dependent upon exercise-induced improvements in vascular endothelial function and nitric oxide (NO) bioavailability. This is notable, because dysfunction of the vascular endothelium and decreased abundance of its major product, NO, have been implicated as early contributors to AD-related cognitive decline and disease progression. Thus, it is possible that exercise may mitigate cognitive function with advancing age and MCI/AD by improving cerebral endothelial function. Nevertheless, due to challenges which we are uniquely poised to overcome, it has yet to be determined if exercise is related to endothelial function within the cerebral circulation, which exhibits unique characteristics compared to the peripheral circulation, where traditional measures are made. Therefore, the first aim of this project will compare endothelial function, measured with both traditional peripheral methods and innovative cerebral methods, to baseline levels of physical activity, and cognitive function in patients with MCI, AD and controls. With the objective of determining if exercise training can be used to mitigate endothelial function and cognitive function in patients with MCI, the second aim of this study will measure endothelial function (cerebral and peripheral) and cognitive function before and after 12 months of high intensity exercise training, or standard therapy. While peripheral endothelial function will be measured with traditional sonographic techniques (e.g. flow-mediated dilation), providing an aspect of generalizability to previous research, cerebral endothelial function will be specifically measured for the first time in MCI/AD with cutting-edge methods that quantify cerebral endothelial function as the change in cerebral blood flow elicited by the intravenous infusion of the nitric oxide synthase inhibitor, L-NMMA. Meanwhile, cognitive function will be assessed with a battery of tests designed to probe cognitive impairment across multiple domains. Thus, the overall goal of the proposed studies is to better understand the link between endothelial function, physical activity, and cognitive function in MCI/AD, thereby determining if cerebral endothelial function and NO bioavailabiity are viable therapeutic targets to limit this debilitating disease.